Cancer cells (relative to normal cells) demonstrate increased rates of glycolysis and pentose cycle activity and slightly decreased rates of respiration but the significance of this is unclear. Recent studies show that glucose de privation preferentially induces cytotoxicity and oxidative stress in cancer cells [Spitz et al., 2000]. Mitochondria have been hypothesized to be the site of prooxidant production during glucose deprivation. If this were true, then defects in cancer cell mitochondrial electron transport chain proteins could be causing altered sensitivity to glucose deprivation-induced cytotoxicity and these defects could be exploited for designing more efficacious combined modality cancer therapies. This proposal tests the hypothesis that mitochondria defects in mammalian cells contributes to increased formation of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide) and this mediates increased susceptibility of human cancer cells to glucose deprivation-induced oxidative stress, relative to normal cells, using intact cells as well as isolated mitochondria from cells subjected to molecular manipulations of mitochondrial Complex II subunits.